Effect of α4β7 blockade on intestinal lymphocyte subsets and lymphoid tissue development

摘要: Integrins are dimeric cell surface molecules composed of α and β subunits that promote cell–cell interactions play important roles in the immune system. Within integrin family, α4β7 displays relative specificity for mucosal immunity has multiple functions including lymphocyte homing, intestinal lymphoid tissue formation, promoting inflammatory responses.1–6 Blockade is an appealing therapy diseases, as effects blocking this pathway will largely be limited to sites. While diverse well described, essential nature these less clear, blockade could result untoward inhibiting homing nonpathogenic lymphocytes formation homeostatic tissues. Mucosal vascular addressin adhesion molecule (MAdCAM-1) binding partner α4β7,1 expressed on high endothelial venules (HEVs) postcapillary vessels intestine. In contrast, by populations hematopoietic cells lymphocytes, natural killer cells, monocytes, inducer (LTi) cells.5–9 A role α4β7/ MadCAM-1 trafficking intestine widely accepted; however, subsets, cellular compartments, conditions which plays role, therefore would affected blockade, clear. Early studies using adoptive transfer labeled identified a Peyer’s patches mucosa uninflamed intestine.2 Later genetically modified mice confirmed absence β7 intestine, had diminished cellularity were decreased.10 However, performed prior appreciation diversity consequently information regarding specific lacking. Moreover, α4β7/MadCAM-1 variable effectiveness animal models inflammation,3,11–14 explained differences strategy, or mechanisms used subpopulations playing pathogenic protective each model. In addition above effects, may affect development tissues during inflammation. critical isolated follicles (ILFs),6 aggregates, adult During bowel disease (IBD), increased numbers aggregates also seen,15–18 observations suggest their dependent interactions. physiologic inflammation, ILFs mediate immunity; conversely, function chronic inflammation clear pathogenic, have been proposed sites containing earliest manifestations IBD.19,20 Thus, aggregate uncontrolled resulting either detrimental beneficial effects. In order better understand processes lost we investigated effect deficiency inflamed contrast current perceptions, observed T-lymphocyte diffuse lamina propria unaffected normal acute injury dextran sodium sulfate (DSS) colitis model. Concordant with B-lymphocyte both loss DSS Furthermore, Foxp3+ T-lymphocytes, like B-lymphocytes, localize aggregates. observations, T-lymphocyte-mediated model was function. Anti-α4β7 did not alter ameliorate DSS-induced colitis, but improve evidenced decreased infiltration into production cyto-kines. These demonstrate differential dependence more targeted than previously appreciated selectively